This project is directed at understanding the cellular mechanisms responsible for the development of immunodeficiency in mice infected with a unique set of murine retroviruses, termed LP-BM5 murine leukemia viruses (MuLV). Animals infected with these viruses rapidly become markedly impaired in their ability to respond to a variety of mitogenic or specific antigenic stimuli in vitro. These abnormalities are also evident in vivo as infected mice sequentially lost the ability to reject skin grafts across MHC class II and MHC class I barriers. These immune defects have been found to result from activation of CD4+ T cells responding to an antigen expressed by B cells. Analyses of the activation process in vitro showed that the B cell determinant responsible for CD4 stimulation is a component of the gag gene encoded by the defective virus genome present in the virus mixture. This molecule behaves like a superantigen in stimulating T cells with restricted T cell receptor beta chain expression in a CD4- and MHC class II-restricted fashion. Stimulation of this T cell subset appears to induce disease secondary to the release of cytokines as progression of the disease is greatly inhibited by treatment of mice with a drug, cyclosporin A (CSA), that inhibits cytokine production. Analyses of cytokine expression by spleens of infected mice revealed a burst of spontaneous cytokine release (IL-2, IL-4, IL-5, IL-10, IFN-Gamma) at one week post infection without the need for mitogenic or antigen stimulation. At later times, spontaneous release was not observed, but following stimulation with Con A, a cytokine profile characteristic of Th2- type helper cells was detected. Preferential activation of this CD4 subset may explain the chronic B cell activation and lymphadenopathy characteristic of this disease, mouse AIDS, (MAIDS).